Animals must maintain a sense of direction and location to efficiently navigate. Humans do this almost effortlessly, unaware of the complex neural mechanisms that generate our spatial knowledge. However, when brain damage disrupts these processes and leaves an individual in a devastating state of chronic disorientation, lost in and disconnected from the physical world, he or she becomes painfully aware of the vital contribution spatial processing makes to our quality of life. This condition, known as topographic disorientation, is commonly caused by stroke-induced damage to retrosplenial cortex (RSP), a component of a conserved mammalian spatial processing circuit. In rodents, the RSP contains head direction (HD) cells; these neurons fire as a function of the animal's HD, operating much like a compass. This finding has been linked to the fact that humans with RSP damage lose their sense of direction. Importantly, the functional and anatomical relationships between the rodent RSP and other nodes in the spatial processing circuit remain unknown; the experiments proposed here will examine these relationships, elucidating the precise contributions of the RSP to spatial coding in the rodent brain and providing clinicians with valuable insights into the etiology of topographic disorientation. The RSP is reciprocally connected with multiple structures that also contain HD cells as well as other types of spatially-tuned neurons. Using an innovative method to reversibly inactivate individual brain regions - Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) - Specific Aim 1 will determine 1) if HD cell activity in the RSP is generated intrinsically or dependent upon input from other HD cell-containing regions and 2) if the RSP influences that activity of downstream spatial signals. This aim will reveal the functional flow of spatial information to and from the RSP. Specific Aim 2 will determine if the RSP displays a functional and anatomical topographic organization in regard to its spatial processing functions as rodent lesion and behavioral studies suggest that HD cells are largely confined to the caudal portion of the RSP. Anterograde and retrograde neuronal tracing experiments will be performed to determine if this potential functional topography maps on to an underlying anatomical topography in which the caudal RSP is more heavily interconnected with other HD cell-containing regions compared to the rostral RSP. Specific Aim 3 will examine the anatomical basis for the previously demonstrated role of the RSP in processing visual landmarks in the environment. Both the RSP and the postsubiculum (PoS) integrate visual information into the spatial processing circuit; this shared function might arise from common visual inputs into these two regions. To test this hypothesis, retrograde tracing experiments will be performed to determine if a single population of cells in the visual system projects to both the RSP and PoS. Together, the results of these proposed experiments will provide clinicians with valuable insights into the systems-level implications of RSP damage, helping them to better diagnose and treat patients suffering from topographic disorientation.